(23S, 25R)-Calcitriol lactone (1a) is a major mammalian metabolite of Vitamin D that has been shown to stimulate bone growth in osteoporotic rats (Seino, Y. et al., Drugs of the Future Vol. 17, p.655 (1992); see also, Japanese Kokai Patent Application No. 04095082A2 (1992)). Compound 1a is therefore useful for the study of, and potentially for the treatment of, osteoporosis and other diseases involving calcium absorption and utilization.
Only very small amounts of Compound 1a are obtainable from natural sources. Practical supply of 1a must therefore rely on chemical synthesis. Several synthetic sequences leading to 1a have been reported (See Hatakeyama et al., J. Chem. Soc., Chem. Commun., 1229 (1992); and Yamamoto et al., J. Org. Chem. Vol. 57, p. 33), (1992). In each case, a critical issue is the construction of the lactone portion comprising carbons 23 through 27, with the stereochemistry at carbons 23 and 25 established in a controlled manner.
Of the several known sequences leading to Compound 1a, the most efficient has been reported by Johnson and Chan (Johnson et al., J. Org. Chem., Vol. 50, p. 2598, (1985), the entire contents of which are hereby incorporated by reference in the present specification). Johnson et al. teach a synthesis of hydrindane triol 2a (R.sup.2 .dbd.CH.sub.2 Ph) in eight chemical steps from aldehyde 5 (R.sup.2 .dbd.CH.sub.2 Ph). These workers furthermore describe the debenzylation of 2a (R.sup.2 .dbd.CH.sub.2 Ph) to tetrol 3a, and oxidation of 3a to keto lactone 4a. The conversion of 4a to 1a is known (Wovkulich et al., J. Org. Chem., Vol. 48, p. 4433, (1983), the entire contents of which are hereby incorporated by reference in the present specification). ##STR1## A bold line denotes a substituent projecting above the plane of the page; a dashed line denotes a substituent projecting below the plane of the page.